Nutrients 2013, 5, 1149-1168; doi:10.3390/nu5041149 OPEN ACCESS
nutrients ISSN 2072-6643 www.mdpi.com/journal/nutrients Review
Is Selenium a Potential Treatment for Cancer Metastasis? Yu-Chi Chen 1, K. Sandeep Prabhu 2,3,4 and Andrea M. Mastro 1,3,4,* 1
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Department of Biochemistry and Molecular Cell Biology, The Pennsylvania State University, University Park, PA 16802, USA; E-Mail:
[email protected] Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; E-Mail:
[email protected] Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802, USA
* Author to whom correspondence should be addressed; E-Mail:
[email protected]; Tel.: +1-814-863-0152; Fax: +1-814-863-7024. Received: 21 February 2013; in revised form: 21 March 2013 / Accepted: 22 March 2013 / Published: 8 April 2013
Abstract: Selenium (Se) is an essential micronutrient that functions as a redox gatekeeper through its incorporation into proteins to alleviate oxidative stress in cells. Although the epidemiological data are somewhat controversial, the results of many studies suggest that inorganic and organic forms of Se negatively affect cancer progression, and that several selenoproteins, such as GPXs, also play important roles in tumor development. Recently, a few scientists have examined the relationship between Se and metastasis, a late event in cancer progression, and have evaluated the potential of Se as an anti-angiogenesis or anti-metastasis agent. In this review, we present the current knowledge about Se compounds and selenoproteins, and their effects on the development of metastasis, with an emphasis on cell migration, invasion, and angiogenesis. In the cancers of breast, prostate, colorectal, fibrosarcoma, melanoma, liver, lung, oral squamous cell carcinoma, and brain glioma, there is either clinical evidence linking selenoproteins, such as thioredoxin reductase-1 to lymph node metastasis; in vitro studies indicating that Se compounds and selenoproteins inhibited cell motility, migration, and invasion, and reduced angiogenic factors in some of these cancer cells; or animal studies showing that Se supplementation resulted in reduced microvessel density and metastasis. Together, these data support the
Nutrients 2013, 5 notion that Se may be an anti-metastastatic element in addition to being a cancer preventative agent. Keywords: selenium; selenoproteins; metastasis; migration; invasion; angiogenesis
Abbreviation Se: selenium Sec: selenocysteine SeMet: selenomethionine MSC: Se-methyl-selenocysteine SECIS: selenocysteine-insertion sequence MeCN: methylselenocyanate SELECT: the Selenium and Vitamin E Cancer Prevention Trial GPX: glutathione peroxidase TXR: thioredoxin reductase SBP: selenium-binding protein MSA: methylseleninic acid VEGF: vascular endothelial growth factor HGF: hepatocyte growth factor IL-1: interlukin-1 IL-8: interlukin-8 SDF-1: stromal cell-derived factor 1 GRO-α: growth-regulated peptide-alpha/growth-regulated oncogene-1 OPN: osteopontin FGF: fibroblast growth factors MMP: matrix metalloproteinase HUVEC: human umbilical vein endothelial cells HIF-1α: hypoxia-induced factor 1alpha SCID mice: severe combined immunodeficient mice Sep15: the 15-KDa selenoprotein uPA: urokinase-type plasminogen activator ECM: extracellular matrix TIMP1: tissue inhibitor of metalloproteinase 1 TIMP2: tissue inhibitor of metalloproteinase 2 PMA: 12-O-tetradecanoylphorbol-13-acetate MT1-MMP: membrane-type 1 matrix metalloproteinase IL-18: interlukin-18 PAI-1: plasminogen activator inhibitor-1 TNFα: tumor necrosis factor alpha IGF II: insulin-like growth factor II
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COX-2: cyclooxygenase-2 iNOS: inducible nitric oxide synthase 1. Introduction Unlike other trace elements that interact with proteins non-covalently, selenium (Se) is an essential and unique micronutrient in that it is co-translationally incorporated into polypeptides in the form of the 21st amino acid, selenocysteine (Sec). Generally, selenoproteins can be classified into three categories. First, there are selenoproteins that have incorporated Sec under a precise process requiring the UGA codon, a specified tRNA (Sec tRNA [Ser]Sec), some regulatory proteins, and the Sec-insertion sequence (SECIS) element [1]. The Sec residues in these selenoproteins are often located in the active site and are critical for their function. There are twenty five selenoproteins identified in the human genome so far [2,3]. The biological functions of some selenoproteins, including glutathione peroxidases (GPXs), deiodinases, and thioredoxin reductases (TXRs), have been studied extensively; while the functions of other selenoproteins, such as selenoprotein K, remain largely unknown. Second, there are proteins that contain selenomethionine (SeMet), in addition to Sec, as a result of their random substitution for cysteine and methionine due to the structural similarity between cysteine and Sec and between methionine and SeMet. Finally, the third class consists of selenium-binding proteins (SBP), which bind Se by some unknown mechanisms [4]. To synthesize Sec, cells have to process various Se compounds obtained from food in order to generate selenophosphate. Selenophosphate interacts with tRNA-bound seryl residues and forms a specific tRNA (Sec tRNA [Ser]Sec). Several Se compounds abundant in plants and animals include SeMet, Sec, Se-methyl-selenocysteine (MSC), γ-glutamyl-Se-methyl-selenocysteine, selenate, and selenite. SeMet, Sec, selenite, and selenite can be converted to the common metabolite, hydrogen selenide (H2Se) that serves as the precursor of selenophosphate (Figure 1). In addition to SeMet, MSC and γ-glutamyl-Se-methyl-Sec also generate methylselenol (CH3SeH). The equilibrium between methylselenol and selenide ensures the use of methylselenol as a Se source when needed [5]. Other than the natural forms of Se, laboratory-synthesized Se compounds, such as methylseleninic acid (MSA), a precursor of methyselenol, have also been extensively studied for their possible therapeutic applications [6]. It is known that when cells generate too much selenide, it reacts with oxygen to produce superoxide, which is toxic to cells [7]. On the other hand, the anti-cancer effects of Se have been shown to involve methylselenol [7,8]. Taken together, various Se compounds may enter the metabolic pathway at different points catalyzed by different enzymes (Figure 1). More importantly, results of several studies show that some effects and/or mechanisms of Se are specific to certain forms of Se [9–11]. For instance, in LNCaP human prostate cancer cells, selenite was more effective in inducing apoptosis than MSA, while DU145 human prostate cancer cells were more sensitive to MSA-induced apoptosis [12]. In addition, due to the easy conversion to selenide, 5 ppm selenite is considered toxic [13]. On the other hand, it has been reported that humans can tolerate much higher SeMet supplementation (7200 μg twice daily for seven days and then a single dose daily for a few weeks) without side effects [13]. The high tolerance and low toxicity profile of organic Se allow the plasma Se to exceed 15 μM, the concentration required to enhance the efficacy and reduce toxicity
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when Se was used in combination with chemotherapeutic drugs in animal models [13]. Therefore, organic Se may have more potential as an anti-cancer therapeutic than inorganic Se. Figure 1. Metabolic pathway of dietary selenium (Se) in humans. Reproduced with permission from [5].
SeMet, selenomethionine; SeCys, selenocysteine; GSSeSG, selenodiglutathione; γ-glutamyl-CH3SeCys, γ-glutamyl-Se-methyl-selenocysteine; H2Se, hydrogen selenide; HSePO32−, selenophosphate; CH3SeCys, Se-methylselenocysteine; CH3SeH, methylselenol; (CH3)2Se, dimethyl selenide; SeO2, selenium dioxide; (CH3)3Set, trimethyl selenonium ion.
For decades, the benefit of Se supplementation on human health has been studied extensively. Primarily, Se supplementation has been considered to be an anti-oxidant endowed with anti-inflammatory and anti-viral activities [1]. In 1985, Clark et al. reported an inverse correlation between the Se content in forage crops in the United States and overall cancer mortality [14]. Supported by these findings, the Nutritional Prevention of Cancer Trial (NPC) was designed to evaluate the advantages of Se supplementation (as Se-enriched yeast) on the recurrence of non-melanoma skin cancer [15]. This trial is now best valued for its secondary findings, which indicated that dietary Se significantly reduced overall cancer mortality and the incidence of prostate, colorectal, lung, and total cancers in male participants during 1983–1993. However, only the reduction in the incidence of total and prostate cancers remained significant in a later analysis in 1996 [16]. It is also noted that Se supplementation had the greatest impact in men with the lowest Se baseline (
